Every day, four thousand women are diagnosed with breast cancer. For most of them, the therapy of choice is the endocrine therapy with tamoxifen, a selective modulator of estrogen receptor (ERα and ERβ). However, one third of these patients develop resistance to this therapy and cancer reappears. We are focused in the study of the role of the extracellular matrix that surrounds tumor cells in the development of endocrine resistance. In this sense, we found that fibronectin, one of the main components of the extracellular matrix, induces tamoxifen resistance through its membrane receptor, β1 integrin. Moreover, we showed that ERαcolocalizes and coimmunoprecipitates with β1 integrin at the plasma membrane of tumor cells. Together with this, estrogens and tamoxifen are able to reduce cell adhesion to fibronectin by a mechanism involving the reduction of adhesion molecules levels and the inhibition of β1 integrin clustering at the cell membrane. We have evidence suggesting that these effects would be mediated by membrane-bound ERα. In this context, the study of the three-dimensional architecture of the adhesion complexes would lead us to know, in an extremely precise way, how ERα is involved in the assembly of these complexes. Moreover, the study of the nanoscale dynamics of adhesion molecules will give us the possibility to describe, with high-temporal resolution, the molecular events that take place during adhesion complexes formation and disassembly in tumor cells under treatment with estrogens or tamoxifen. Overall, the results of this project will provide a detailed characterization of the communication between extracellular matrix and tumor cells and the role of estrogens and tamoxifen in it. This approach is completely original in the field of cancer biology and we are convinced that this new focus will be a point of inflection in the research for an efficient way to resensitize women to endocrine therapy.